1. Field of the Invention
This invention relates to novel 3-halovinylglycines and their amino acid dipeptide and oligopeptide conjugates which display antibacterial activity.
2. Brief Description of Disclosures in the Art
Alanine racemases, which are pyridoxal-requiring enzymes uniquely present in bacteria and essential for biosynthesis of the D-alanine component of the bacterial cell wall, are prime targets for the design of specific inhibitors as new and effective antibacterial agents. In general, the potency of such inhibitors can be correlated with antibacterial activity, assuming effective transport into the bacterial cytoplasm.
Known inhibitors for alanine racemase include cycloserine, 1-aminoethylphosphonic acid, and particularly the .beta.-substituted alanines which are active site directed (suicide type) irreversible inhibitors. For recent reviews see: Neuhaus, F. C.; Hammes, W. P. Pharmacol. Ther. 1981, 14, 265-319; Walsh, C. T. Tetrahedron 1982, 38, 871-909; and Walsh, C. T. Ann. Rev. of Biochemistry 1984, 53, 493-535. Inhibition by the B-substituted alanines is characterized by high partition ratios (ca 800)--that is 800 conversions of inhibitor to pyruvate and reconstitution of active enzyme for every lethal event leading to irreversibly inactivated enzyme. See Wang, E.; Walsh, C. T. Biochemistry 1978, 17, 1313-1321.
The 3-halovinylglycines are also irreversible inhibitors of alanine racemase and as such interfere with bacterial cell wall biosynthesis. Furthermore, they exhibit low partition ratios (D-3-chlorovinylglycine: partition ratio of about 1) indicative of much greater lethal efficiency in comparison to the .beta.-substituted alanines.
In the literature, new compounds are constantly being scrutinized as potential enzyme inhibitors, for example, racemic 3-chlorovinylglycine or 2-amino-3-chloro-3-butenoic acid is described in Archives of Biochemistry and Biophysics, Vol. 213, No. 2, February, pp. 695-707 (1982) as not being an inactivator for cystathionine synthetase in the synthesis of cystathionine from serine. However, no discussion of the optically active isomers or their activity as alanine racemase inhibitors is given.
In the field of antibacterial agents, new compounds and classes of chemical agents are constantly being searched for in an effort to obtain more effective, broader spectrum antibacterials, which display less toxic side effects.
What is particularly desired and what is an object of this invention are newer classes of antibacterials which are distinctly efficacious towards infectious gram-positive and various gram negative bacteria.